加速发现强效呼吸道合胞病毒融合抑制剂。
Accelerated Discovery of Potent Fusion Inhibitors for Respiratory Syncytial Virus.
机构信息
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30303, United States.
出版信息
ACS Infect Dis. 2020 May 8;6(5):922-929. doi: 10.1021/acsinfecdis.9b00524. Epub 2020 Apr 20.
Abstract
A series of five benzimidazole-based compounds were identified using a machine learning algorithm as potential inhibitors of the respiratory syncytial virus (RSV) fusion protein. These compounds were synthesized, and compound in particular exhibited excellent potency with an EC value of 5 nM. This new scaffold was then further refined leading to the identification of compound , which exhibited a 10-fold improvement in activity with an EC value of 0.5 nM.
摘要
采用机器学习算法鉴定了一系列五种苯并咪唑类化合物作为呼吸道合胞病毒（RSV）融合蛋白的潜在抑制剂。这些化合物被合成，特别是化合物 表现出优异的 效价，EC 值为 5 nM。然后进一步优化这个新骨架，鉴定出化合物 ，其活性提高了 10 倍，EC 值为 0.5 nM。
相似文献
1
Accelerated Discovery of Potent Fusion Inhibitors for Respiratory Syncytial Virus.
ACS Infect Dis. 2020 May 8;6(5):922-929. doi: 10.1021/acsinfecdis.9b00524. Epub 2020 Apr 20.
2
Discovery of Ziresovir as a Potent, Selective, and Orally Bioavailable Respiratory Syncytial Virus Fusion Protein Inhibitor.
J Med Chem. 2019 Jul 11;62(13):6003-6014. doi: 10.1021/acs.jmedchem.9b00654. Epub 2019 Jun 26.
3
Small molecules VP-14637 and JNJ-2408068 inhibit respiratory syncytial virus fusion by similar mechanisms.
Antimicrob Agents Chemother. 2005 Jun;49(6):2460-6. doi: 10.1128/AAC.49.6.2460-2466.2005.
4
Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability.
Bioorg Med Chem Lett. 2007 Feb 15;17(4):895-901. doi: 10.1016/j.bmcl.2006.11.063. Epub 2006 Dec 1.
5
Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.
J Med Chem. 2021 Apr 8;64(7):3658-3676. doi: 10.1021/acs.jmedchem.0c01882. Epub 2021 Mar 17.
6
Synthesis and Biological Evaluation of Novel (thio)semicarbazone-Based Benzimidazoles as Antiviral Agents against Human Respiratory Viruses.
Molecules. 2020 Mar 25;25(7):1487. doi: 10.3390/molecules25071487.
7
Respiratory syncytial virus fusion inhibitors. Part 6: an examination of the effect of structural variation of the benzimidazol-2-one heterocycle moiety.
Bioorg Med Chem Lett. 2007 Sep 1;17(17):4784-90. doi: 10.1016/j.bmcl.2007.06.065. Epub 2007 Jun 26.
8
Discovery of methylsulfonyl indazoles as potent and orally active respiratory syncytial Virus(RSV) fusion inhibitors.
Eur J Med Chem. 2017 Sep 29;138:1147-1157. doi: 10.1016/j.ejmech.2017.07.032. Epub 2017 Jul 20.
9
Design and Synthesis of 2-(1-Alkylaminoalkyl)pyrazolo[1,5-a]pyrimidines as New Respiratory Syncytial Virus Fusion Protein Inhibitors.
Chem Pharm Bull (Tokyo). 2020;68(4):345-362. doi: 10.1248/cpb.c19-00895.
10
Design, synthesis, in vitro and in vivo anti-respiratory syncytial virus (RSV) activity of novel oxizine fused benzimidazole derivatives.
Eur J Med Chem. 2021 Nov 15;224:113684. doi: 10.1016/j.ejmech.2021.113684. Epub 2021 Jul 5.
引用本文的文献
1
Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses.
Viruses. 2024 Nov 14;16(11):1776. doi: 10.3390/v16111776.
2
On the additive artificial intelligence-based discovery of nanoparticle neurodegenerative disease drug delivery systems.
Beilstein J Nanotechnol. 2024 May 15;15:535-555. doi: 10.3762/bjnano.15.47. eCollection 2024.
3
Improving drug discovery with a hybrid deep generative model using reinforcement learning trained on a Bayesian docking approximation.
J Comput Aided Mol Des. 2023 Nov;37(11):507-517. doi: 10.1007/s10822-023-00523-3. Epub 2023 Aug 8.
4
Treatment of Respiratory Viral Coinfections.
Epidemiologia (Basel). 2022 Feb 23;3(1):81-96. doi: 10.3390/epidemiologia3010008.
5
Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents.
Pharmaceuticals (Basel). 2021 Dec 15;14(12):1307. doi: 10.3390/ph14121307.
6
Anno 2021: Which antivirals for the coming decade?
Annu Rep Med Chem. 2021;57:49-107. doi: 10.1016/bs.armc.2021.09.004. Epub 2021 Nov 3.
本文引用的文献
1
Accelerated Discovery of Novel Ponatinib Analogs with Improved Properties for the Treatment of Parkinson's Disease.
ACS Med Chem Lett. 2020 Mar 12;11(4):491-496. doi: 10.1021/acsmedchemlett.9b00612. eCollection 2020 Apr 9.
2
A Phase 2, Randomized, Double-blind, Placebo-Controlled Trial of Presatovir for the Treatment of Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic-Cell Transplant Recipients.
Clin Infect Dis. 2020 Dec 31;71(11):2777-2786. doi: 10.1093/cid/ciz1166.
3
Error Tolerance of Machine Learning Algorithms across Contemporary Biological Targets.
Molecules. 2019 Jun 4;24(11):2115. doi: 10.3390/molecules24112115.
4
A Machine Learning Approach for Predicting HIV Reverse Transcriptase Mutation Susceptibility of Biologically Active Compounds.
J Chem Inf Model. 2018 Aug 27;58(8):1544-1552. doi: 10.1021/acs.jcim.7b00475. Epub 2018 Jul 17.
5
Antiviral Activity of Oral JNJ-53718678 in Healthy Adult Volunteers Challenged With Respiratory Syncytial Virus: A Placebo-Controlled Study.
J Infect Dis. 2018 Jul 24;218(5):748-756. doi: 10.1093/infdis/jiy227.
6
Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series.
Lancet Glob Health. 2017 Oct;5(10):e984-e991. doi: 10.1016/S2214-109X(17)30344-3.
7
Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor.
Nat Commun. 2017 Aug 1;8(1):167. doi: 10.1038/s41467-017-00170-x.
8
Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.
Lancet. 2017 Sep 2;390(10098):946-958. doi: 10.1016/S0140-6736(17)30938-8. Epub 2017 Jul 7.
9
Drug candidates and model systems in respiratory syncytial virus antiviral drug discovery.
Biochem Pharmacol. 2017 Mar 1;127:1-12. doi: 10.1016/j.bcp.2016.09.014. Epub 2016 Sep 19.
10
GS-5806 Inhibits a Broad Range of Respiratory Syncytial Virus Clinical Isolates by Blocking the Virus-Cell Fusion Process.
Antimicrob Agents Chemother. 2015 Dec 14;60(3):1264-73. doi: 10.1128/AAC.01497-15.
Zotero 插件